Introduction Advanced squamous cell anal cancer (aSCAC) is a rare and aggressive disease. No targeted therapies are currently approved and no standard therapies after first line are currently available. Molecular characteristics of SCAC are poorly explored. Immune checkpoint inhibitors (ICI) showed signs of activity in previous phase I/II trials, but predictive and prognostic biomarkers are lacking. High TMB and PD-L1 were associated to better response to ICI in other malignancies, but few data are available for SCAC. Anti-EGFR have been tested given the well-known rarity of KRAS mutations in SCAC, with encouraging results. Earlier preclinical evidence suggests possible synergism between cetuximab (cet) and PD-L1 blockade Materials and methods In the phase II randomized trial CARACAS (NCT03944252), we tested avelumab (ave) alone (Arm A) or with cet (Arm B) in pretreated aSCAC, being overall response rate (ORR) the primary endpoint. With one-sided alpha error set at 0.05 and power of 80%, at least 4 responses out of 27 patients per arm had to be observed to declare the study positive. On pre-treatment tumor tissue samples, we assessed HPV status, PD-L1 expression, microsatellite status, tumor mutational burden (TMB) and next generation sequencing (NGS). Tumor-infiltrating lymphocytes (TILs) were characterized on HE-stained samples. Translational analyses were conducted on the 100% of patients enrolled in the clinical trial since all of them received ICI. Primary objective of the TranslaCARACAS study was to describe the clinical outcomes of ICI in the CARACAS trial population according to molecular analyses. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular characteristics to individuate new prognostic biomarkers in SCAC. Results In the clinical trial, the Arm B reached the primary endpoint (ORR 17%). High TMB (3 10 mutations per megabase) was related to better OS (HR=0.09; 95%CI 0.01-0.68; p=0.019), showing the same trend in PFS (HR=0.44; 95%CI=0.15-1.27; p=0.129). High expression of PD-L1 (>40 measured with combined positive score, CPS) conferred significantly longer OS (HR=2.19; 95%CI=0.92-5.19; p=0.075) and PFS (HR=2.35; 95%CI=1.09-5.1; p=0.03). High TILs (>1.2) did not affect OS (HR=0.77; 95%CI=0.42-1.4; p=0.39) nor PFS (HR=1.19; 95%CI=0.57-2.48; p=0.645). Combined together and with high TILs, high TMB and PD-L1identified pts with significantly better prognosis in OS (HR=0.43; 95%CI=0.21-0.87; p=0.019) and PFS (HR=0.48; 95%CI=0.23-1.00; p=0.051). Remarkable responses were also observed in patients with high PD-L1 expression and TMB Conclusions To our knowledge, TranslaCARACAS was the first study to document prognostic role of TMB and PD-L1 in mSCAC treated with ICI. Further investigation in larger cohorts is warranted to confirm our findings
introduzione Il cancro anale a cellule squamose in stadio avanzato (aSCAC) è una malattia rara e aggressiva. Non sono attualmente approvate terapie target e non sono attualmente disponibili terapie standard dopo la prima linea. Le caratteristiche molecolari dell'aSCAC sono poco esplorate. Gli inibitori dei checkpoint immunitari (ICI) hanno mostrato segni di attività in precedenti studi di fase I/II, ma mancano biomarcatori predittivi e prognostici. Elevati livelli di TMB e PD-L1 sono stati associati a una migliore risposta all'ICI in altre neoplasie, ma sono disponibili pochi dati relativamente all'aSCAC. Gli anti-EGFR sono stati testati data la ben nota rarità delle mutazioni KRAS nell'aSCAC, con risultati incoraggianti. Evidenze precliniche precedenti suggeriscono un possibile sinergismo tra cetuximab (cet) e blocco PD-L1 Materiali e metodi Nello studio randomizzato di fase II CARACAS (NCT03944252), abbiamo testato avelumab (ave) da solo (Braccio A) o con cet (Braccio B) in aSCAC pretrattato, essendo il tasso di risposta globale (ORR) l'endpoint primario. Con un errore alfa unilaterale fissato a 0,05 e una potenza dell'80%, è stato necessario osservare almeno 4 risposte su 27 pazienti per braccio per dichiarare lo studio positivo. Su campioni di tessuto tumorale pre-trattamento, abbiamo valutato lo stato dell'HPV, l'espressione di PD-L1, lo stato dei microsatelliti, il carico mutazionale del tumore (TMB) e il sequenziamento di nuova generazione (NGS). I linfociti infiltranti il tumore (TIL) sono stati caratterizzati su campioni preparati con ematossilina-eosina. Le analisi traslazionali sono state condotte sul 100% dei pazienti arruolati nello studio clinico poiché tutti hanno ricevuto ICI. L'obiettivo primario dello studio TranslaCARACAS era descrivere i risultati clinici degli ICI nella popolazione dello studio CARACAS in accordo alle analisi molecolari. Gli obiettivi secondari erano valutare la sopravvivenza libera da progressione (PFS) e la sopravvivenza globale (OS) in base alle caratteristiche molecolari per individuare nuovi biomarcatori prognostici nello SCAC. Risultati Nello studio clinico, il braccio B ha raggiunto l'endpoint primario (ORR 17%). L'elevato TMB (3-10 mutazioni per megabase) era correlato a una migliore OS (HR=0,09; IC 95% 0,01-0,68; p=0,019), mostrando lo stesso andamento nella PFS (HR=0,44; IC 95%=0,15-1,27; p=0.129). Un'elevata espressione di PD-L1 (>40 misurata con punteggio positivo combinato, CPS) ha conferito OS (HR=2,19; 95%CI=0,92-5,19; p=0,075) e PFS (HR=2,35; 95%CI=1,095,p=0,03) significativamente più lunghi. TILs elevati (>1,2) non hanno influenzato la OS (HR=0,77; 95%CI=0,42-1,4; p=0,39) né la PFS (HR=1,19; 95%CI=0,57-2,48; p=0,645). Combinati insieme e con TILs, elevati livelli di TMB e PD-L1 identificavano un sottogruppo di pazienti con prognosi significativamente migliore in OS (HR=0.43; 95%CI=0.21-0.87; p=0.019) e PFS (HR=0.48; 95%CI=0.23- 1,00; p=0,051). Risposte notevoli sono state osservate anche in pazienti con elevata espressione di PD-L1 e TMB Conclusioni A nostra conoscenza, TranslaCARACAS è stato il primo studio a documentare il ruolo prognostico di TMB e PD-L1 in mSCAC trattati con ICI. Ulteriori indagini in coorti più ampie sono giustificate per confermare i nostri risultati
Profiling molecolare esteso del carcinoma anale a cellule squamose nella popolazione di uno studio di fase 2: analisi traslazionali dello studio “CARACAS” / Prete, ALESSANDRA ANNA. - (2022 Feb 21).
Profiling molecolare esteso del carcinoma anale a cellule squamose nella popolazione di uno studio di fase 2: analisi traslazionali dello studio “CARACAS”.
PRETE, ALESSANDRA ANNA
2022
Abstract
Introduction Advanced squamous cell anal cancer (aSCAC) is a rare and aggressive disease. No targeted therapies are currently approved and no standard therapies after first line are currently available. Molecular characteristics of SCAC are poorly explored. Immune checkpoint inhibitors (ICI) showed signs of activity in previous phase I/II trials, but predictive and prognostic biomarkers are lacking. High TMB and PD-L1 were associated to better response to ICI in other malignancies, but few data are available for SCAC. Anti-EGFR have been tested given the well-known rarity of KRAS mutations in SCAC, with encouraging results. Earlier preclinical evidence suggests possible synergism between cetuximab (cet) and PD-L1 blockade Materials and methods In the phase II randomized trial CARACAS (NCT03944252), we tested avelumab (ave) alone (Arm A) or with cet (Arm B) in pretreated aSCAC, being overall response rate (ORR) the primary endpoint. With one-sided alpha error set at 0.05 and power of 80%, at least 4 responses out of 27 patients per arm had to be observed to declare the study positive. On pre-treatment tumor tissue samples, we assessed HPV status, PD-L1 expression, microsatellite status, tumor mutational burden (TMB) and next generation sequencing (NGS). Tumor-infiltrating lymphocytes (TILs) were characterized on HE-stained samples. Translational analyses were conducted on the 100% of patients enrolled in the clinical trial since all of them received ICI. Primary objective of the TranslaCARACAS study was to describe the clinical outcomes of ICI in the CARACAS trial population according to molecular analyses. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular characteristics to individuate new prognostic biomarkers in SCAC. Results In the clinical trial, the Arm B reached the primary endpoint (ORR 17%). High TMB (3 10 mutations per megabase) was related to better OS (HR=0.09; 95%CI 0.01-0.68; p=0.019), showing the same trend in PFS (HR=0.44; 95%CI=0.15-1.27; p=0.129). High expression of PD-L1 (>40 measured with combined positive score, CPS) conferred significantly longer OS (HR=2.19; 95%CI=0.92-5.19; p=0.075) and PFS (HR=2.35; 95%CI=1.09-5.1; p=0.03). High TILs (>1.2) did not affect OS (HR=0.77; 95%CI=0.42-1.4; p=0.39) nor PFS (HR=1.19; 95%CI=0.57-2.48; p=0.645). Combined together and with high TILs, high TMB and PD-L1identified pts with significantly better prognosis in OS (HR=0.43; 95%CI=0.21-0.87; p=0.019) and PFS (HR=0.48; 95%CI=0.23-1.00; p=0.051). Remarkable responses were also observed in patients with high PD-L1 expression and TMB Conclusions To our knowledge, TranslaCARACAS was the first study to document prognostic role of TMB and PD-L1 in mSCAC treated with ICI. Further investigation in larger cohorts is warranted to confirm our findingsFile | Dimensione | Formato | |
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Descrizione: “Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: translational analyses of the “CARACAS” study.”
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